Prostate cancer is currently the most common cancer among American men. Regulation of prostatic cell growth is largely controlled by androgens including especially dihydrotestosterone (DHT). This compound is synthesized from the male hormone testosterone by the enzyme 5-alpha reductase which is encoded in the prostate by the SRD5A2 gene. The etiology of prostate cancer appears to include increased steroid 5-alpha reductase activity particularly across racial/ethnic groups which are at very different risk for prostate cancer, such as high-risk African-Americans and lower risk Asians, the two extreme groups for risk. We have identified and characterized genetic variability in the SRD5A2 gene among various racial/ethnic groups in the US and between prostate cancer cases and controls. These investigations made use of a large multiethnic cohort in Los Angeles and Hawaii. We propose to build on and expand our studies of the SRD5A2 gene and prostate cancer by epidemiologic, genetic and biochemical methods. It is our overall hypothesis that genetic variation at the SRD5A2 locus plays a significant role in predisposition to and progression of prostate cancer and in explaining the racial/ethnic variation of risk. To this end, we intend to investigate the following interrelated six specific aims: 1) To identify all constitutional (""""""""germline"""""""") DNA variations across the entire SRD5A2 gene that might contribute to predisposition to prostate cancer; 2) To determine the relationship between each variant identified in Specific Aim 1 to prostate cancer risk in for racial/ethnic populations: 4) To identify somatic mutations in the SRD5A2 gene involved in prostate cancer progression; 5) To characterize the biochemical properties of the somatic DNA genetic variants identified in Specific aims 1 and 4 in an in vitro model system; 6) To determine the contribution of somatic DNA genetic variants in the SRD5A2 gene to prostate cancer progression within and across racial/ethnic groups. Therefore, we will investigate the molecular basis of predisposition to prostate cancer and its progression in a multidisciplinary study rooted in molecular epidemiology with significant implications for presymptomatic identification of at-risk individuals, targeted chemoprevention and improved treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068581-09
Application #
6633089
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Silkensen, Shannon M
Project Start
1995-09-30
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2006-05-31
Support Year
9
Fiscal Year
2003
Total Cost
$456,302
Indirect Cost
Name
University of Southern California
Department
Biochemistry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Pearce, C Leigh; Van Den Berg, David J; Makridakis, Nick et al. (2008) No association between the SRD5A2 gene A49T missense variant and prostate cancer risk: lessons learned. Hum Mol Genet 17:2456-61
Novelli, Giuseppe; Margiotti, Katia; Chiocca, Anna Maria et al. (2004) Pharmacogenetics of human androgens and prostate cancer--an update. Pharmacogenomics 5:283-94
Mehrian-Shai, Ruty; Reichardt, Juergen K V (2004) A renaissance of ""biochemical genetics""? SNPs, haplotypes, function, and complex diseases. Mol Genet Metab 83:47-50
Makridakis, Nick M; Reichardt, Juergen K V (2004) Molecular epidemiology of androgen-metabolic loci in prostate cancer: predisposition and progression. J Urol 171:S25-8; discussion S28-9
Allen, Naomi E; Reichardt, Juergen K V; Nguyen, Hannah et al. (2003) Association between two polymorphisms in the SRD5A2 gene and serum androgen concentrations in British men. Cancer Epidemiol Biomarkers Prev 12:578-81
Pearce, Celeste L; Makridakis, Nick M; Ross, Ronald K et al. (2002) Steroid 5-alpha reductase type II V89L substitution is not associated with risk of prostate cancer in a multiethnic population study. Cancer Epidemiol Biomarkers Prev 11:417-8
Hsing, A W; Chen, C; Chokkalingam, A P et al. (2001) Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 10:1077-82
Makridakis, N M; Reichardt, J K (2001) Molecular epidemiology of hormone-metabolic loci in prostate cancer. Epidemiol Rev 23:24-9
Makridakis, N M; Reichardt, J K (2001) Multiplex automated primer extension analysis: simultaneous genotyping of several polymorphisms. Biotechniques 31:1374-80
Novelli, G; Margiotti, K; Sangiuolo, F et al. (2001) Pharmacogenetics of human androgens and prostatic diseases. Pharmacogenomics 2:65-72

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